Histamine plays a role in allergic responses, is involved in the regulation of gastric acid secretion and also is a neurotransmitter. Histamine is inactivated by oxidative deamination in a diamine oxidase catalyzed reaction or by N-methylation in a histamine N-methyltransferase (HNMT) catalyzed reaction. The product of the N-methylation, N-methylhistamine, is converted by monoamine oxidase to N-methyl imidazole acetic acid. HNMT is an S-adenosyl-L-methionine dependent cytosolic enzyme that contains 292 amino acids and has a relative molecular weight of 33 kDa.
N-methylation is the major process responsible for termination of the neurotransmitter actions of histamine in the brain as well as a major pathway for histamine metabolism in bronchial epithelium. HNMT also is expressed highly in the human kidney where a 6-fold interindividual variation in activity is observed. HNMT activity in human red blood cells varies as a result of a common genetic polymorphism. Scott, M. C. et al., Clin. Pharmacol. Ther., 43:256-262 (1988); and Price, R. A. et al., Genet. Epidemiol., 10:123-131 (1993). Approximately 70%-90% of the variance in activity is due to inheritance.